Chronic exposure to a hypoxic environment is associated with physiological changes which includes a decrease in hemoglobin affinity for oxygen (increased P50) as well as an increase in the hematocrit. Since these adaptations may have evolved in response to stresses such as anemia, they may be inappropriate for adjustment to high altitude or to chronic hypoxemia due to lung gas exchange failure. Previous investigators have studied the effects of small increases in hematocrit on exercise tolerance, but the effects of large increases in hematocrit or altered P50 on O2 transport during exercise are still abscure. I propose to study the effects of moderate to severe polycythemia (hematocrit = 55 to 75%) on oxygen exchange in the lung, on oxygen transport to the tissues, and on oxygen consumption in muscle during graded exercise in the animal model. Effects of polycythemia on cardiac output and on the distribution of blood flow to tissues such as skeletal muscle, kidney, intestine and the heart will be studied during exercise to determine whether high hematocrits can act to limit oxygen delivery to the tissues. The possible role of polycythemia in limiting oxygen transport from the microcirculation to the mitochondria due to a diffusion barrier or a redistribution of perfusion in relation to metabolic activity will also be investigated. The role of combined polycythemia and exercise during hypoxia will also be studied in relationship to oxygen diffusion in the lung, using the multiple inert gas elimination technique. Effects of altered hemoglobin affinity on exercise performance and on oxygen transport to the periphery will be studied during exercise to determine whether a decreased P50 is advantageous to oxygen delivery during hypoxia. Sodium cyanate will be used to decrease P50. These studies are of significance in the understanding of man's ability to work and, indeed, survive at extreme altitude. In addition, these studies are of relevance in the management of patients with chronic arterial hypoxemia due to pulmonary gas exchange failure. Hence, they are justified on a scientific as well as a clinical standpoint.